Sleepiness that persists despite episodes of prolonged sleep (viz., hypersomnolence) negatively impacts morbidity and mortality. The sleep and circadian sciences have identified environmental, biological, and genetic factors that influence hypersomnolence, yet, little of this knowledge has been translated into the clinic. Valid and reliable means of assessment and biomarker(s) for hypersomnolence are lacking. Psychostimulants that enhance wake remain the default mainstays of treatment. Their efficacies depend on heightening the brain's excitatory monoamine signaling, but they can be ineffective and fraught with side effects. They are prescribed routinely which reinforces heuristic constructs that posit loss of function in the brain's wake- promoting networks as the principal arbiter of hypersomnolence. The alternative hypothesis - namely, that hypersomnolence reflects a gain in function in brain mechanisms subserving sleep - has its advocates. Naturally occurring putative somnogens that accumulate after restricting sleep include adenosine, prostaglandins, cytokines, the diazepam binding inhibitor (DBI), and oleamides, but none are proven to cause pathological sleepiness in humans. The knowledge gained has therefore not translated into rational, treatment alternatives for hypersomnolence. Human conditions in which hypersomnolence emerges sui generis, e.g., the `primary hypersomnias' (PH), afford a unique opportunity to derive novel mechanistic insights into `natural' sleep per se, because they bypass interpretative confounds of experimental paradigms that include sleep restriction. After excluding known causes of hypersomnolence in 32 PH patients, we have reported on an endogenous peptidergic bioactivity in their cerebrospinal fluids that mimics the actions of sedative-hypnotics and anesthesia. This physiology is reversible with benzodiazepine (BZD) antagonists in vitro, and translates in vivo to vigilance improvements that appear superior to conventional medications. Our major goal here is to advance mechanistic understanding of this putative sleep-inducing GABA-ergic bioactivity by determining its: 1) specificity to persistent and episodic hypersomnolence in PH and Kleine-Levin syndrome, respectively, vs. sleepiness associated with obstructive sleep apnea; 2) reliance upon the a-1 GABAA receptor subunit known to mediate sedation in vivo, and site of action relative to this receptor's BZD binding pocket through physiological interrogation of molecularly engineered receptor variants in vitro ; and 3) identity. These mechanistic details of pathological hypersomnolence promise to change medical practice by way of improved diagnostics and therapeutics.